The invention is directed to various therapeutic uses of small molecule compounds having either hepatocyte growth factor/scatter factor (HGF/SF) activity, or the property of inhibiting the activity of HGF/SF. Such compounds have the potential for the treatment of conditions and diseases in which modulation of cellular proliferation, among other activities, is desired.
Scatter factor (SF; also known as hepatocyte growth factor [HGF], and hereinafter referred to and abbreviated as HGF/SF) is a pleiotropic growth factor that stimulates cell growth, cell motility, morphogenesis and angiogenesis. HGF/SF is produced as an inactive monomer (xcx9c100 kDa) which is proteolytically converted to its active form. Active HGF/SF is a heparin-binding heterodimeric protein composed of a 62 kDa xcex1 chain and a 34 kDa xcex2 chain. HGF/SF is a potent mitogen for parenchymal liver, epithelial and endothelial cells (Matsumoto, K, and Nakamura, T., 1997, Hepatocyte growth factor (HGF) as a tissue organizer for organogenesis and regeneration. Biochem. Biophys. Res. Commun. 239, 639-44; Boros, P. and Miller, C. M., 1995, Hepatocyte growth factor: a multifunctional cytokine. Lancet 345, 293-5). It stimulates the growth of endothelial cells and also acts as a survival factor against endothelial cell death (Morishita, R, Nakamura, S, Nakamura, Y, Aoki, M, Moriguchi, A, Kida, I, Yo, Y, Matsumoto, K, Nakamura, T, Higaki, J, Ogihara, T, 1997, Potential role of an endothelium-specific growth factor, hepatocyte growth factor, on endothelial damage in diabetes. Diabetes 46:138-42). HGF/SF synthesized and secreted by vascular smooth muscle cells stimulate endothelial cells to proliferate, migrate and differentiate into capillary-like tubes in vitro (Grant, D. S, Kleinman, H. K., Goldberg, I. D., Bhargava, M. M., Nickoloff, B. J., Kinsella, J. L., Polverini, P., Rosen, E. M., 1993, Scatter factor induces blood vessel formation in vivo. Proc. Natl. Acad. Sci. U S A 90:1937-41; Morishita, R., Nakamura, S., Hayashi, S., Taniyama, Y., Moriguchi, A., Nagano, T., Taiji, M., Noguchi, H., Takeshita, S., Matsumoto, K., Nakamura, T., Higaki, J., Ogihara, T., 1999, Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension 33:1379-84). HGF/SF-containing implants in mouse subcutaneous tissue and rat cornea induce growth of new blood vessels from surrounding tissue. HGF/SF protein is expressed at sites of neovascularization including in tumors (Jeffers, M., Rong, S., Woude, G. F., 1996, Hepatocyte growth factor/scatter factor-Met signaling in tumorigenicity and invasion/metastasis. J. Mol. Med. 74:505-13; Moriyama, T., Kataoka, H., Koono, M., Wakisaka, S., 1999, Expression of hepatocyte growth factor/scatter factor and its receptor c-Met in brain tumors: evidence for a role in progression of astrocytic tumors Int. J. Mol. Med. 3:531-6). These findings suggest that HGF/SF plays a significant role in the formation and repair of blood vessels under physiologic and pathologic conditions. Further discussion of angiogenic proteins may be found in U.S. Pat. Nos. 6,011,009 and 5,997,868, both of which are incorporated herein by reference in their entireties.
Modulation of cellular proliferation by exogenously-supplied therapeutic agents has been offered as a new approach for the prophylaxis and/or treatment of various conditions and diseases in which limited cellular proliferation, or, in contrast, excessive proliferation of cells, is responsible for pathology, or at least for the prolongation of rebound from a pathological state to homeostasis. For example, the duration of wound healing, normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction, development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs, and vascularization of grafted or transplanted tissues, organs, or wound healing, may be accelerated by promoting cellular proliferation, particularly of vascular cells.
In other cases where abnormal or excessive cellular proliferation is the cause of pathology, such as in dysproliferative diseases including cancer, inflammatory joint and skin diseases such as rheumatoid arthritis, and neovascularization in the eye as a consequence of diabetic retinopathy, suppression of cellular proliferation is a desired goal in the treatment of these and other conditions. In either case, therapy to promote or suppress proliferation may be beneficial locally but not systemically, and for a particular duration, and proliferation modulating therapies must be appropriately applied.
In co-pending application Ser. No. 09/606,628, filed Jun. 29, 2000, incorporated herein by reference in its entirety, peptide mimetics with HGF/SF-like, proliferative activity and particularly angiogenic activity, as well as other agents, particularly peptide HGF/SF antagonists which inhibit cellular proliferation and, in particular, angiogenesis, were described. Such peptides have uses, for example, in the treatment of inflammatory diseases, cancer, neovascularization, cardiac ischemia, wound healing, and other conditions in which modulation of cellular proliferation including blood vessel growth is therapeutically beneficial, as described above.
It is toward the identification of small organic molecules with HGF/SF activity, or those that inhibit HGF/SF activity, that the present invention is directed.
The citation of any reference herein should not be construed as an admission that such reference is available as xe2x80x9cPrior Artxe2x80x9d to the instant application.
In one broad aspect, the present invention is directed to methods for the modulation of hepatocyte growth factor/scatter factor (HGF/SF) activities in a mammal for the treatment of any of a number of conditions or diseases in which either HGF/SF has a therapeutically useful role, or in which the activity of endogenous HGF/SF is desirably inhibited or abrogated. Such modulation is achieved by the administration to the mammal of a compound of the invention in an amount effective to achieve the desired outcome. In one embodiment, the compounds of the invention modulate the activity of the HGF/SF receptor, c-Met. In a further embodiment, the compounds of the invention bind to c-Met.
In the instance where HGF/SF activity is desirable, certain compounds of the invention have been found to mimic or agonize the biological activities of HGF/SF, and thus are useful in the treatment, for example, of conditions or diseases in which enhanced cellular or vascular proliferation is desirable, among other desirable activities of HGF/SF. Such conditions or diseases include hepatic disease, renal disease, bone regeneration, hair growth, promoting wound or tissue healing, or augmenting or restoring blood flow to ischemic tissues such as the heart following myocardial infarction. Such compounds may be administered systemically or locally to particular tissues or organs, in order to achieve the desired systemic or local effect.
Such desirable activities also includes induction of proliferation of endothelial cells, induction of anti-apoptotic activity, induction of scatter activity, or any combination of the foregoing activities. In a preferred embodiment, any one of these activities is reduced or inhibited in the presence of exogenous c-Met receptor by a compound of the invention.
The compounds of the invention useful for mimicking or agonizing HGF/SF activity are characterized by being non-peptide, non-protein organic molecules with one or more of the activities of promoting proliferation of endothelial cells in vitro or in vivo, promoting angiogenesis in vitro or in vivo, increasing angiogenesis in wounds in vivo, promoting the growth of tumor cells in vitro or in vivo, promoting scatter, promoting anti-apoptotic activity, or inducing gene expression of angiogenic-cascade-related genes such as but not limited to IL-8 and angiopoietin-2. Preferred are compounds in which the aforementioned activity is inhibited or competed in the presence of exogenously-added c-Met receptor. The compounds may bind to c-Met. The present invention embraces the use of all such molecules for treatment of various conditions or diseases in which increased or enhanced HGF/SF activity is desirable. In one embodiment, the compounds of the invention have a molecular weight of under 1,000 Daltons, preferably above about 200 Daltons to about 1,000 Daltons; more preferably between about 300 Daltons and about 750 Daltons, and most preferably between about 300 Daltons and about 500 Daltons.
Thus, a method is provided for increasing hepatocyte growth factor/scatter factor (HGF/SF) activities in a mammal by administration to the mammal an effective amount of a compound having a molecular weight below 1,000 Daltons, the compound exhibiting HGF/SF-like activity in at least one of the following HGF/SF activity assays:
induction of proliferation of endothelial cells in vitro or in vivo;
induction of angiogenesis in vitro or in vivo;
increasing angiogenesis in wounds in vivo;
promoting tumor growth;
inducing gene expression of angiogenic-cascade-related genes such as but not
limited to IL-8 and angiopoietin-2;
inducing anti-apoptotic activity; or
inducing scatter activity.
In a preferred embodiment, the HGF/SF activity of the foregoing compound is inhibited in the presence of c-Met. In another preferred embodiment, the compounds bind to c-Met.
A compound of the invention may exhibits HGF/SF-like activity in at least two of the aforementioned HGF/SF activity assays, or in at least three of the HGF/SF activity assays, or in at least four said HGF/SF activity assays, or in at least five of the HGF/SF activity assays, or in at least six of the HGF/SF activity assays or in all of the HGF/SF activity assays. The compound preferably has a molecular weight between about 300 Daltons and about 750 Daltons, more preferably between about 300 Daltons and about 500 Daltons.
In another embodiment, the invention is directed to a method for the prophylaxis or treatment in a mammal of hepatic disease, renal disease, bone regeneration, hair growth, promoting wound or tissue healing, promoting vascularization of a tissue, promoting vascularization of an ischemic tissue, promoting vascularization of a tissue susceptible to ischemia, or augmenting or restoring blood flow to ischemic tissues such as the heart following myocardial infarction comprising administered systemically or locally to particular tissues or organ in need thereof an effective amount of a compound having a molecular weight between below about 1,000 Daltons, the compound exhibiting HGF/SF-like activity in at least one HGF/SF activity assays:
induction of proliferation of endothelial cells in vitro or in vivo;
induction of angiogenesis in vitro or in vivo;
increasing angiogenesis in wounds in vivo;
promoting tumor growth;
inducing gene expression of angiogenic-cascade-related genes such as but not limited to IL-8 and angiopoietin-2;
inducing anti-apoptotic activity; or
inducing scatter activity.
In a preferred embodiment, the HGF/SF activity of the foregoing compound is inhibited in the presence of c-Met.
A compound of the invention may exhibits HGF/SF-like activity in at least two of the aforementioned HGF/SF activity assays, or in at least three of the HGF/SF activity assays, in at least five said HGF/SF assays, in at least six said HGF/SF assays, or in at least four said HGF/SF activity assays, or in all of the HGF/SF activity assays. The compound preferably has a molecular weight between about 200 Daltons and about 750 Daltons, more preferably between about 300 Daltons and about 500 Daltons.
The invention is also directed to a method for inhibiting the activity of hepatocyte growth factor/scatter factor (HGF/SF) in a mammal comprising administering to the mammal an effective amount of a compound having a molecular weight below about 1,000 Daltons, the compound exhibiting HGF/SF inhibitory or antagonistic activity in at least one of the following HGF/SF activity assays:
inhibiting proliferation of endothelial cells in vitro or in vivo;
inhibiting the growth of tumor cells in vitro or in vivo;
inhibiting scatter of normal or tumor cells; or
inhibiting anti-apoptotic activity.
In a preferred embodiment, the HGF/SF inhibitory activity of the foregoing compound occurs in the presence of exogenously added HGF/SF or in cells or tissues in which HGF/SF is expressed or induced.
A compound of the invention may exhibit HGF/SF inhibitory activity in at least two of the aforementioned HGF/SF activity inhibition assays, or in at least three of the HGF/SF activity inhibition assays, or in all of the HGF/SF activity inhibition assays. The compound preferably has a molecular weight between about 200 Daltons and about 750 Daltons, more preferably between about 300 Daltons and about 500 Daltons.
In yet another embodiment, a method is provided for the prophylaxis or treatment in a mammal of a condition of disease selected from the group consisting of excessive cellular proliferation, angiogenesis, a dysproliferative disease, cancer, metastasis, inflammatory disease, diabetic retinopathy, inflammatory joint disease, and inflammatory skin disease comprising administering to a mammal an effective amount of a compound having a molecular weight below about 1,000 Daltons, said compound exhibiting HGF/SF inhibitory or antagonistic activity in at least one of the following HGF/SF activity inhibition assays:
inhibiting proliferation of endothelial cells in vitro or in vivo;
inhibiting the growth of tumor cells in vitro or in vivo;
inhibiting scatter of normal or tumor cells; and
inhibiting anti-apoptotic activity.
In a preferred embodiment, the HGF/SF inhibitory activity of the foregoing compound occurs in the presence of exogenously added HGF/SF or in cells or tissues in which HGF/SF is expressed or induced.
A compound of the invention may exhibit HGF/SF inhibitory activity in at least two of the aforementioned HGF/SF activity inhibition assays, or in at least three of the HGF/SF activity inhibition assays, or in all of the HGF/SF activity inhibition assays. The compound preferably has a molecular weight between about 200 Daltons and about 750 Daltons, more preferably between about 300 Daltons and about 500 Daltons.
In another embodiment, the invention is directed to a method for the use for any of the aforementioned purposes of compounds that modulate HGF/SF activity with the general formula I: 
wherein
R3 and R5 are independently or together a straight-chain or branched C1-C6 alkyl optionally substituted with a cyano or halogen, halogen, trifluoromethyl or difluoromethyl groups;
R1 is hydrogen, methyl, CO-Aryl, SO2-Aryl, CO-heteroaryl, or CO-alkyl; and R4 is CH2-Aryl, halogen, arylcarbonylvinyl or S-heteroaryl.
Certain of the compounds of Formula I are novel, and the present invention is also directed to all such novel compounds with an activity as described herein.
The invention is also directed to a pharmaceutical composition comprising at least one compound of Formula I, in a pharmaceutically-acceptable carrier, for any of the uses described herein.
Non-limiting example of modulators of HGF/SF activity of Formula I include the following compounds, most of which, as will be seen in the examples below, exhibit HGF/SF agonist activity.
3-(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)-1-(4-chlorophenyl)prop-2-en-1-one [4-(2,6-dichlorobenzyl)-3,5-dimethyl-1H-pyrazol-1-yl][3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]methanone (4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-1-yl)(3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)methanone 4-(2-chloro-6-fluorobenzyl)-1-((3,4-dichlorophenyl)sulfonyl)-3,5-dimethyl1H-pyrazole 4-(2-chloro-6-fluorobenzyl)-1,3,5-trimethyl-1H-pyrazole 4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole (4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)(3-(2,6-dichlorophenyl)isoxazole-4-carbohydrazide) 3-(4-(2,6-dichlorobenzyl)-3,5-dimethyl-1H-pyrazol-1-yl)propanenitrile 3,5-di(tert-butyl)-4-(2-chloro-6-fluorobenzyl)-1H-pyrazole (4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-1-yl)(2,6-dichlorophenyl)methanone 1-(4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-1-yl)2,2-dimethylpropan-1-one (4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-1-yl)(4-chlorophenyl)methanone (4-(2-chloro-6-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-1-yl)(2-thienyl)methanone (4-chlorophenyl)(3,5-dimethyl-4-((1-methyl-1H-imidazol-2-yl)thio)-1H-pyrazol-1-yl) methanone
In another embodiment, the invention is directed to methods for the use for the aforementioned purposes of compounds that modulate HGF/SF activity with the general formula II: 
wherein
R5 is a C1 to C6 branched or straight-chained alkyl group;
R3 is a substituted or unsubstituted Aryl group;
R1 is hydrogen or a C1 to C4 straight-chained, branched or cycloalkyl group;
R2 is COCH2ONCH-Aryl; heteroaryl, COCH2CH2Aryl; Aryl; COS-Aryl; CO-Heteroaryl; C1 to C4 straight-chained alkyl, branched alkyl, or cycloalkyl; or wherein R1 and R2 form a cyclic group of 5 or 6 carbon atoms.
Certain of the compounds of Formula II are novel, and the present invention is directed to all such novel compounds with an activity as described herein.
The invention is also directed to a pharmaceutical composition comprising at least one compound of Formula II, in a pharmaceutically-acceptable carrier, for any of the uses described herein.
Most of the compounds of Formula II exhibit HGF/SF antagonist or inhibitory activity, as will be seen in the examples below. Non-limiting examples of compounds of Formula II include
Nxe2x80x24,5-dimethyl-Nxe2x80x24-(5-nitro-2-pyridyl)-3-(2,6-dichlorophenyl)isoxazole-4-carbohydrazide Nxe2x80x24-(2-(((2,4-dichlorobenzylidene)amino)oxy)acetyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide Nxe2x80x24-(3-(3,4,5-trimethoxyphenyl)propanoyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide 2-nitrophenyl 2-((3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)carbonyl)hydrazine-1-carbothioate Nxe2x80x24-((2-methyl-1,3-thiazol-4-4yl)carbonyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-4carbohydrazide N1-((2-((3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)carbonyl)hydrazino)(methylthio)methylidene)benzene-1-sulfonamide Nxe2x80x24-(2,4,6-trichlorophenyl)-3-3(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide Nxe2x80x24,3-di(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide Nxe2x80x24-(3,5-dichloro-4-pyridyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide Nxe2x80x24-phenyl-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide Nxe2x80x24, Nxe2x80x24,5-trimethyl-3-(2,6-dichlorophenyl)isoxazole-4-carbohydrazide N4-azepan-1-yl-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxamide Nxe2x80x24-(6-(trifluoromethyl)-2-pyridyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide Nxe2x80x24-(3,3-diethoxypropanoyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide
In a further embodiment, the invention is directed to methods for the use for any of the aforementioned purposes of compounds that modulate HGF/SF activity with the general formula III: 
wherein
R1 is SO2Alkyl, SO2-Aryl, CO-t-Butyl, COAryl, CONHAlkyl; CONHAryl; and
R3 is CHCH-heteroaryl; phenoxyphenyl; heteroaryl; or Aryl substituted heteroaryl.
Certain of the compounds of Formula III are novel, and the present invention is directed to all such novel compounds with an activity as described herein.
The invention is also directed to a pharmaceutical composition comprising at least one compound of Formula III, in a pharmaceutically-acceptable carrier, for any of the uses described herein.
These compounds generally exhibit HGF/SF stimulatory or agonist activity. Non-limiting examples of compounds of Formula III include
(4-chlorophenyl)[3-(2-(2-thienyl)vinyl)-1H-pyrazol-1-yl]methanone; 1-(methylsulfonyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole; 2,2-dimethyl-1-(3-(2-(2-thienyl)vinyl)-1H-pyrazole1-yl)propan1-one N-methyl-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide (4-chlorophenyl)(3-(3-phenylisoxazol-5-yl)-1H-pyrazol-1-yl)methanone (4-chlorophenyl)(3-(3-(4-chlorophenyl)-5-methylisoxazol-4-yl)-1H-pyrazol-1-yl)methanone (4-chlorophenyl)(3-(5-(2-thienyl)-2-thienyl)-1H-pyrazol1-yl)methanone (2,4-dichlorophenyl)(3-(5-(2,4-difluorophenyl)-2-furyl)-1H-pyrazol-1-yl)methanone N1-phenyl-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide (4-chlorophenyl)(3-(2-(5-(2-thienyl)-2-thienyl)-4-methyl-1,3-thiazol-5-yl)-1H-pyrazol-1-yl)methanone (3-benzhydryl-1H-pyrazol-1-yl)(4-chlorophenyl)methanone N1-(4-chlorophenyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide (4-chlorophenyl)(3-(2-methylimidazo(1,2-a)pyridin-3-yl)-1H-pyrazol-1-yl)methanone 2-chloro-6-(4-(1-(4-chlorobenzyl)-1H-pyrazol-3-yl)phenoxy)benzonitrile 1-((4-chlorophenyl)sulfonyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole
In a further embodiment, the invention is directed to methods for the use for any of the aforementioned purposes of compounds that modulate HGF/SF activity with the general formula IV: 
Wherein
R1 is Aryl or Heteroaryl; and
R2 is one or more halogen, nitro, C1 to C4 straight-chained alkyl, branched alkyl, or cycloalkyl, or C1 to C4 alkyloxy groups.
Certain of the compounds of Formula IV are novel, and the present invention is directed to all such novel compounds with an activity as described herein.
The invention is also directed to a pharmaceutical composition comprising at least one compound of Formula IV, in a pharmaceutically-acceptable carrier, for any of the uses described herein.
The compounds in this group may be HGF/SF agonists or antagonists. Non-limiting examples of modulators of Formula IV include:
1-(4-chloro-3-methylphenyl)-3-(2,6-dichlorophenyl)-prop-2-en-1-one 1-(4-chloro-3-methylphenyl)-3-(2-chlorophenyl)prop-2-en-1-one 3-(2-chloro-6-fluorophenyl)-1-(4-chloro-3-methylphenyl)prop-2-en-1-one 3-(4-bromo-2-thienyl)-1-(3,4-dichlorophenyl)prop-2-en-1-one 3-(4-bromo-2-thienyl)-1-(4-chloro-3-methylphenyl)prop-2-en-1-one 3-(4-bromo-2-thienyl)-1-(4-fluorophenyl)prop-2-en-1-one 3-(4-bromo-2-thienyl)-1-(4-chlorophenyl)prop-2-en-1-one 1-(4-chlorophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one 3-(1,3-benzodioxol-5-yl)-1-(4-bromophenyl)prop-2-en-1-one 3-(3-phenoxy-2-thienyl)-1-(2-thienyl)prop-2-en-1-one 3-(3-bromo-4-methoxyphenyl)-1-phenylprop-2-en-one 3-(3,4-dichlorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one 1-(4-chlorophenyl)-3-(3,4-dichlorophenyl)prop-2-en-1-one 1-(4-chlorophenyl)-3-(3,5-dichloro-2-hydroxyphenyl)prop-2-en-1-one 1-(2-chlorophenyl)-3-(3,5-dichloro-2-hydroxyphenyl)prop-2-en-1-one 3-(4-chlorophenyl)-1-(2,6-dichlorophenyl)prop-2-en-1-one 1-(4-bromophenyl)-3-(4-chlorophenyl)prop-2-en-1-one 1-(2-chlorophenyl)-3-(2,6-dichlorophenyl)prop-2-en-1-one 1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)prop-2-en-1-one 3-(2,6-dichlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one 3-(4-chloro1-methyl-1H-pyrazol-3-yl)-1-[4-(trifluoromethyl)phenyl]prop-2-en-1-one 3-(2,4-dichlorophenyl)-1-(2-methylphenyl)prop-2-en-1-one 3-(2,6-dichlorophenyl)-1-(2-methylphenyl)prop-2-en-1-one 3-(3,4-dichlorophenyl)-1-(2-methylphenyl)prop-2-en-1-one 3-(5-bromo-2-hydroxyphenyl)-1-(3-methylphenyl)prop-2-en-1-one 3-(5-bromo-2-hydroxyphenyl)-1-(4-methylphenyl)prop-2-en-1-one 3-(2,4-dichlorophenyl)-1-(3-methylphenyl)prop-2-en-1-one 3-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one 1-[4-amino-2-(methylthio)-1,3-thiazol-5-yl]-3-(4-chlorophenyl)prop-2-en-1-one 1-(4-chlorophenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one 1-benzo[b]thiophen-3-yl-3-(4-chlorophenyl)prop-2-en-1-one 1,3-di(5-nitro-3-thienyl)prop-2-en-1-one 1-(4-bromophenyl)-3-(3,5-difluorophenyl)prop-2-en-1-one 3-(3,5-difluorophenyl)-1-(3-nitrophenyl)prop-2-en-1-one
The foregoing general and specific structures of compounds with HGF/SF activity are merely illustrative of compounds of the invention with the desired activities, and are in no way limiting.
In a further embodiment, the invention is directed to pharmaceutical compositions comprising any one or a combination of the foregoing compounds, together with a pharmaceutically-acceptable carrier, for use in any of the aforementioned purposes.
In a further embodiment, the aforementioned compounds with activities of promotion of cellular proliferation or angiogenesis are useful for promoting vascularization of a tissue, particularly of an ischemic tissue or a tissue susceptible to ischemia.
Prophylaxis or treatment may be provided by contacting the tissue with an effective angiogenic amount of an agent of the invention. Contact may be provided by any appropriate means to deliver an effective amount of the agent for a duration to achieve the desired results. By way of non-limiting example, topical application may be applied to the desired target, or by infusion, bathing, or implantation of a sustained delivery device. For systemic administration, oral or parenteral routes may be employed. The target cells or tissue may be, for example, a transplanted or grafted tissue or organ such as skin, heart, vascular tissue or kidney, an ischemic organ, such as a heart following myocardial infarction or angina, a tissue or organ damaged by wounding, surgical intervention, vascular tissue, neural tissue, a wound, ulcer, etc. The cells may be, by way of non-limiting example, epithelial cells, endothelial cells, and smooth muscle cells, and tissues and organs comprising such cells. Promotion of growth and/or regeneration of neural tissue, teeth, and other tissues are embraced herein. Preferred cells, organs and tissues comprise the c-Met receptor.
The aforementioned compounds with HGF/SF activity are also desirably useful for the treatment of various hepatic diseases including cirrhosis and liver failure; various renal diseases including renal failure. The compounds are also useful for inducing bone regeneration.
In another broad aspect of the invention, undesirable activities of HGF/SF in vivo may be therapeutically inhibited by the administration to a mammal of an effective amount of certain compounds of the invention for the treatment of various conditions and diseases generally involved in cellular proliferation and angiogenesis, among others. Inhibition of HGF/SF is desired, for example, in the treatment of dysproliferative diseases such as cancer and metastases, as well as various inflammatory diseases such as inflammatory joint and skin diseases. Other activities include but are not limited to inhibition of endothelial cell proliferation, inhibition of angiogenesis, angiostasis, tumoricidal activity, and any combination of the foregoing. In a further embodiment, the agents inhibit activity in the presence of exogenously-added or in cells in which activity is present or induced. Abnormal vascular proliferation such as occurs in diabetic retinopathy is also treatable by the methods of the invention.
The compounds of the invention useful for inhibiting HGF/SF activity are characterized by being non-peptide, non-protein, organic molecules with one or more of the activities of inhibiting proliferation of endothelial cells in vitro or in vivo, inhibiting the growth, scatter or metastasis of tumor cells in vitro or in vivo, inhibiting scatter, or inhibiting anti-apoptotic activity. Preferred are compounds in which such activities are exhibitable in the presence of exogenously-added HGF/SF. The present invention embraces the use of all such molecules for treatment of various conditions or diseases in which decreased or inhibited HGF/SF activity is desirable.
In a further aspect, the invention is directed to pharmaceutical compositions comprising any one or a combination of any of the foregoing compounds, together with a pharmaceutically-acceptable carrier.
The aforementioned compounds are useful for the treatment of dysproliferative or angiogenic diseases, such as but not limited to a tumor or metastasis, or psoriasis, or a tissue or organ involved in inflammatory diseases such as rheumatoid arthritis, the eye involved in neovascularization such as results from chronic diabetes, an abnormal growth such as keloid formation during wound healing, or a desired intentional disruption of cellular proliferation such as to prevent the genesis or maturation of a developing organ or tissue. Methods of treatment include application of a compound of the invention to the desired target site(s), in the form of a pharmaceutical composition comprising one or more compounds of the invention.
The foregoing general and specific structures of compounds with HGF/SF inhibitory or antagonizing activity are merely illustrative of compounds of the invention with the desired activities, and are in no way limiting.
These and other aspects of the present invention will be better appreciated by reference to the following drawings and Detailed Description.